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Immunomodulation of cytosolic DNA sensors by type i interferon adjuvants in macrophages of newborn in vitro infected with HSV-1 and HIV-1

Grant number: 16/01269-1
Support type:Scholarships in Brazil - Master
Effective date (Start): May 01, 2016
Effective date (End): January 31, 2018
Field of knowledge:Biological Sciences - Immunology
Principal Investigator:Maria Notomi Sato
Grantee:Anna Julia Pietrobon
Home Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Newborns (NBs) have more susceptibility to infections, even for bacterial or viral compared to adults. Some infections that have no vaccination coverage, the NBs can show significate susceptibility, as for human immunodeficiency virus (HIV-1) and occasionally for herpes simplex virus (HSV-1). Despite the relative immunological immaturity, newborn cells can stablish an adequate immunological response upon in vitro stimulation with adjuvants. Until this moment, there is scarce knowledge regarding function of macrophages in response to HIV-1 and HSV-1 infections in the neonatal period and the possible efficacy of type I interferon (IFN-I) adjuvants. The purpose of this project is to evaluate the profile of DNA cytosolic sensors expression in monocyte-derived macrophages from umbilical cord (newborns) and adults in the HSV-1 and HIV-1 infection as well as the immunomodulatory potential of the IFN-I adjuvants. For that, the expression of cytosolic DNA sensors, such as, DDX41 (DEAD box polypeptide 41), DAI (DNA-dependent activator of IFN-regulatory factors), IFI16 (gamma-interferon-inducible protein 16), AIM2 (absent in melanoma 2), STING (stimulator of interferon genes), cGAS (Cyclic GMP-AMP synthase) and the exonuclease TREX1 (3-prime repair exonuclease 1) will be evaluated in the monocyte-derived macrophages from cord blood and peripheral blood of healthy adults. It will be evaluated the capacity of the Toll-like receptor 3 (TLR3/poly IC-RIG), TLR7/8 (CL097) and of STING (3'3'-cGAMP) agonists to enhance cytosolic DNA sensors expression followed by HIV-1 and HSV-1 in vitro infection. Moreover, after the in vitro viral infection it will be analyzed the antiviral factors expression, such as APOBEC3G (apolipoprotein B mRNA editing enzyme catalytic polypeptide like 3A), SAMHD1 (SAM domain and HD domain-containing protein 1) and MX2 (myxovirus resistance protein 2), signaling pathways STING-IRF3 (interferon regulatory factor-3)-IFN-² and AIM2 (absent in melanoma 2)-Caspase1-IL-1² (interleucina 1²) and the capacity of IRF3 nuclear translocation. The influence of the sensor IFI16 to activate the inflamassomes, AIM2 and NLRP3 (NACHT-, LRR- and PYD-containing protein 3) will be also assessed in the in vitro infection by these viruses. Our findings might contribute to a better understanding of the mechanisms involved in the innate immunity activation in newborns, which can provide subsides for the search of vaccine adjuvants to enhance the antiviral response.